ETHYNYLESTRADIOL INCREASES EXPRESSION AND ACTIVITY OF RAT LIVER MRP3

RUIZ ML; VILLANUEVA SSM; LUQUITA MG; VORE M; MOTTINO AD; CATANIA VA

Drug Metabolism and Disposition

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2006 vol. 34 p. 1030 - 1034

0090-9556

We evaluated the effect of ethynylestradiol (EE) administration (5mg/kg b.wt. s.c., for 5 consecutive days) on the expression andactivity of multidrug resistance-associated protein 3 (Mrp3) in rats.Western blotting analysis revealed decreased Mrp2 (41%) andincreased Mrp3 (200%) expression by EE. To determine the functionalimpact of up-regulation of Mrp3 versus Mrp2, we measuredthe excretion of acetaminophen glucuronide (APAP-glu), a commonsubstrate for both transporters, into bile and perfusate in therecirculating isolated perfused liver (IPL) model. APAP-glu wasgenerated endogenously from acetaminophen (APAP), which wasadministered as a tracer dose (2 mol/ml) into the perfusate.Biliary excretion of APAP-glu after 60 min of perfusion was reducedin EE-treated rats (80%). In contrast, excretion into theperfusate was increased by EE (45%). Liver content of APAP-gluat the end of the experiment was reduced by 36% in the EE group.The total amount of glucuronide remained the same in bothgroups. Taken together, these results indicate that up-regulationof Mrp3 led to an exacerbated basolateral versus canalicular excretionof conjugated APAP in IPL. We conclude that inducedexpression of basolateral Mrp3 by EE may represent a compensatorymechanism to prevent intracellular accumulation of commonMrp substrates, either endogenous or exogenous, due to reducedexpression and activity of apical Mrp2.